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Sequence Variants with Large Effects on Cardiac Electrophysiology and Disease

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Sequence Variants with Large Effects on Cardiac Electrophysiology and Disease ARTICLE https://doi.org/10.1038/s41467-019-12682-9 OPEN Sequence variants with large effects on cardiac electrophysiology and disease Kristjan Norland1,12, Gardar Sveinbjornsson1,2,12, Rosa B. Thorolfsdottir1, Olafur B. Davidsson1, Vinicius Tragante1,3, Sridharan Rajamani1, Anna Helgadottir1, Solveig Gretarsdottir1, Jessica van Setten3, Folkert W. Asselbergs3,4,5, Jon Th. Sverrisson6, Sigurdur S. Stephensen7, Gylfi Oskarsson7, Emil L. Sigurdsson8,9, Karl Andersen10,11, Ragnar Danielsen10, Gudmundur Thorgeirsson1,10,11, Unnur Thorsteinsdottir1,11, David O. Arnar1,10,11, Patrick Sulem1, Hilma Holm1, Daniel F. Gudbjartsson1,2* & Kari Stefansson 1,11* 1234567890():,; Features of the QRS complex of the electrocardiogram, reflecting ventricular depolarisation, associate with various physiologic functions and several pathologic conditions. We test 32.5 million variants for association with ten measures of the QRS complex in 12 leads, using 405,732 electrocardiograms from 81,192 Icelanders. We identify 190 associations at 130 loci, the majority of which have not been reported before, including associations with 21 rare or low-frequency coding variants. Assessment of genes expressed in the heart yields an addi- tional 13 rare QRS coding variants at 12 loci. We find 51 unreported associations between the QRS variants and echocardiographic traits and cardiovascular diseases, including atrial fibrillation, complete AV block, heart failure and supraventricular tachycardia. We demon- strate the advantage of in-depth analysis of the QRS complex in conjunction with other cardiovascular phenotypes to enhance our understanding of the genetic basis of myocardial mass, cardiac conduction and disease. 1 deCODE genetics/Amgen Inc., Reykjavik, Iceland. 2 School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland. 3 Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. 4 Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK. 5 Health Data Research UK and Institute of Health Informatics, University College London, London, UK. 6 Department of Internal Medicine, Akureyri Hospital, Eyrarlandsvegur, 600 Akureyri, Iceland. 7 Department of Paediatric Cardiology, Children’s Hospital, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 8 Department of Family Medicine, University of Iceland, Reykjavik, Iceland. 9 Department of Development, Primary Health Care of the Capital Area, Reykjavik, Iceland. 10 Division of Cardiology, Internal Medicine Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 11 Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 12These authors contributed equally: Kristjan Norland, Gardar Sveinbjornsson. *email: [email protected]; [email protected] NATURE COMMUNICATIONS | (2019) 10:4803 | https://doi.org/10.1038/s41467-019-12682-9 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-12682-9 he QRS complex (Fig. 1) of the electrocardiogram (ECG) is demonstrate the advantage of analysing 12 leads of the ECG and Ta summation of electrical activity in the heart during identify rare protein-coding variants in genes that can improve ventricular depolarisation. It represents electrical activation the understanding of risk and progression of heart disease and of the left and right ventricles of the heart, propagated through help direct future studies. the specialised conduction system1, which includes the His bundle, right and left bundle branches and the Purkinje network. Normal ventricular depolarisation is a rapid process activating Results different ventricular myocardial segments in a precise temporal QRS associations. We performed a GWAS on 81,192 indivi- sequence, resulting in a narrow QRS complex with a character- duals, testing 32.5 million common and rare (MAF > 0.01%) istic pattern on the 12-lead ECG1. Deviation from the norm has SNPs and indels for association with 123 QRS complex para- been associated with sudden cardiac arrest (prolonged ventricular meters (Supplementary Fig. 1, Supplementary Tables 1 and 2). activation time)2,3 and mortality in the general population Thevariantswereidentified by whole-genome sequencing (prolonged QRS duration)4 and among individuals free of car- 15,220 Icelanders and imputed into 151,677 long-range phased diovascular disease (low QRS voltage)5. individuals and their relatives16. We adjusted the threshold for Many traits and diseases affect the morphology of the QRS genome-wide significance with a weighted Bonferroni proce- complex, including body habitus, primary conduction abnorm- dure, using as weights the predicted functional impact of alities, hypertrophy and dilatation of the ventricles, myocardial association signals17 (Supplementary Table 3). Sequence var- infarction, pericardial effusion and lung disease6. Measures of the iants at 130 loci (MAF > 0.1%) associate with at least one QRS QRS complex have been used as prognostic indicators and mar- complex parameter. Using conditional analysis, we identified kers of heart disease severity, such as heart failure7, ventricular 60 secondary signals at 32 of the loci, resulting in 190 distinct hypertrophy8 and amyloidosis9. associations (Supplementary Data 1 and 2). We replicated Prior genome-wide association studies (GWAS) of the QRS associations at all 54 reported QRS loci with at least one of the complex were limited to testing QRS duration and voltage criteria 123 QRS parameters (Supplementary Data 3, Supplementary reflecting left ventricular hypertrophy, yielding sequence variants Table 4; P < 0.05/123 = 4.1 × 10−4). – at 58 loci with minor allele frequency (MAF) >4%10 15. Among the 190 variants that associate with QRS parameters, To gain a better understanding of the molecular mechanism of 159 are common (MAF > 5%) with effects ranging in magnitude ventricular conduction, we perform a large GWAS of ten mea- from 0.04 to 0.14 standard deviations (s.d.), 14 are low-frequency sures of the QRS complex in 12 leads from ECGs of 81,192 (1% < MAF ≤ 5%) with effects ranging from 0.11 to 0.35 s.d., and individuals. These ten measures are the Q, R and S wave ampli- 17 are rare (MAF ≤ 1%) with effects ranging from 0.19 to 1.9 s.d. tudes and durations, QRS complex area and duration, ventricular We found genome-wide significant associations with 115 of activation time, and the distance from the peak of the R wave to 123 QRS parameters tested. There were no genome-wide the nadir of the S wave (QRS p-2-p). We analyse each measure for significant associations with eight Q wave amplitude and duration 12 ECG leads: limb leads (I–III), augmented limb leads (aVR, parameters, of which four had relatively few available measure- aVL, aVF) and precordial leads (V1–V6). We also analyse three ments (N < 15,000). Of the 190 variants, 160 associate genome- other parameters: mean QRS duration over 12 leads, the Cornell wide significantly with more than one QRS parameter. The R voltage criterion and the Sokolow-Lyon voltage criterion. In total, amplitude is the QRS measure that captures the most associations we analyse 123 QRS complex parameters and this results in the (N = 96), followed by QRS area (N = 85) and R duration (N = identification of 190 associations between the QRS complex and 76), while the Cornell voltage criterion captures the fewest (N = variants at 130 loci, for which we further assess effects on seven 18) (Supplementary Fig. 2). Some of the variants associate only echocardiographic traits and 22 cardiovascular diseases. We with the R amplitude (N = 16), R duration (N = 9), S amplitude QRS dur. VAT aVR aVL R amp. QRS peak-to-peak I V6 V5 V1 V2 V3 V4 + QRS area –– III II aVF R dur. Q amp. S amp. Q dur. S dur. Fig. 1 ECG wave and the QRS complex. We denote QRS measures used in the analysis with grey lines. We illustrate the different viewpoints of the 12 ECG leads in the upper-right corner. Amp. amplitude, Dur. duration, VAT ventricular activation time 2 NATURE COMMUNICATIONS | (2019) 10:4803 | https://doi.org/10.1038/s41467-019-12682-9 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-12682-9 ARTICLE (N = 9), QRS area (N = 5), QRS p-2-p (N = 4) or ventricular Replication. We assessed the associations of unreported QRS activation time (N = 4). variants in (1) QRS parameters similar to ours from 19,885 ECGs For the R amplitude, we identified most associations with lead of participants in the UK Biobank and (2) a published GWAS14 V1 (N = 47, Fig. 2). Fifteen variants associate only with the R on four QRS measures from up to 73,518 participants. amplitude in lead V1. We identified more than twice as many Using data from the published GWAS on QRS duration and associations for the QRS p-2-p amplitude in lead aVR than in any three voltage criteria14, we tested variants that associated genome- other lead (N = 47). For the QRS area, we identified most wide significantly in the Icelandic material with any of these four associations with lead II (N = 43); with lead V3 for QRS duration parameters. We tested seven variants and all replicated (P < 0.05 (N = 39); with lead V5 for R duration (N = 33), S duration (N = and the same direction of effects, Supplementary Data 6). In the 33) and S amplitude (N = 31); and with lead V6 for ventricular smaller UK Biobank data, we tested variants that we expected to activation time (N = 28), Q amplitude (N = 24) and Q duration replicate (over 99% power). Of 13 variants tested, all had the same (N = 9). Across all QRS measures, we observed the fewest direction of effects in both datasets and 11 replicated (P < 0.05 associations with leads III and aVL. and the same direction of effects, Supplementary Data 7). The genes harbouring the missense and loss-of-function variant associations likely encode proteins that play roles in the Associations with echocardiographic traits. Using echocardio- biology of the QRS complex.
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